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Print version ISSN 0034-7094
Rev. Bras. Anestesiol. vol.52 no.1 Campinas Jan./Feb. 2002
Cytokines and anesthesia *
Citocinas y anestesia
João Batista Santos Garcia, TSA, M.D.I; Adriana Machado Issy, TSA, M.D.II; Rioko Kimiko Sakata, TSA, M.D.II
IPós-Graduando da UNIFESP, Professor
Adjunto de Anestesiologia da UFMA (Universidade do Maranhão)
IIProfessora Adjunta de Anestesiologia da UNIFESP
BACKGROUND AND OBJECTIVES: Cytokines can
be stimulated and released by surgical injury, trauma, infection, inflammation
and cancer. High cytokine circulating levels may lead to complications and delay
of postoperative recovery. This study review and summarizes available information
CONTENTS: Cytokines are polypeptide molecules produced by a wide variety of cells, which seem not to play a role in homeostasis under normal conditions. These mediators are responsible for local or systemic responses and produce immune, metabolic, hemodynamic, endocrine and neural changes. They may activate beneficial biologic responses, such as antimicrobial function stimulation, wound healing, myelostimulation and substrate mobilization. However, abundant cytokine secretion is associated to deleterious effects, such as hypotension, organ failure and death.
CONCLUSIONS: In closing this review, it is clear that cytokines have a fundamental role as metabolic, hormonal, immune and hematological response mediators; that there is a therapeutic potential for their expression block; and that anesthesia may interfere in their activation. However, several questions are still to be answered and further studies are needed to explain cytokine actions not only for experimental, but also for clinical purposes.
Key Words: CYTOKINES
JUSTIFICATIVA Y OBJETIVOS: Varios trabajos
han abordado las citocinas que pueden ser estimuladas y liberadas por lesión
quirúrgica, trauma, infección, inflamación y cáncer. Niveles
elevados circulantes de las citocinas parece que tienen implicaciones en el
aparecimiento de complicações y retardo de la recuperación pós-operatoria
de pacientes. El objetivo de la presente revisión es resumir las informaciones
hoy disponibles sobre las citocinas.
CONTENIDO: Las citocinas son moléculas polipeptídicas producidas por una gran variedad de células y parecen no tener función en la homeostasis, bajo condiciones normales. Esas mediadoras son responsables por respuestas locales o sistémicas, generando alteraciones inmunológicas, metabólicas, hemodinámicas, endócrinas y neurales. Pueden activar respuestas biológicas benéficas, como estimulación de la función antimicrobiana, cicatrización de heridas, mieloestimulación y movilización de substratos. Sin embargo, la secreción abundante de citocinas está asociada a efectos deletéreos como hipotensión arterial, falencia de órganos y muerte.
CONCLUSIONES: Al concluir esta revisión, se hace evidente que las citocinas desempeñan un papel de fundamental importancia como mediadores de respuestas metabólicas, hormonales, inmunológicas y hematológicas, que hay potencial terapéutico con el bloqueo de su expresión y que la anestesia puede interferir de alguna forma en su activación. Sin embargo, muchas preguntas no están aún respondidas y deben ser realizados estudios en los próximos años buscando esclarecer las acciones de las citocinas no solo para la experimentación, mas también para la práctica clínica.
Recent studies have called attention on the role of cytokines in several different areas of medical knowledge. After early investigations have showed the existence of lymphocyte-produced protean factors (hence the name lymphokines), later studies purified, characterized and individualized cytokines especially those synthesized by leucocytes and which act primarily on other leucocytes (hence the name interleukines). Through technique improvement involving molecular cloning, it was more recently possible to accurately identify structure and properties of this protein group, which is best called cytokines. Such term may be employed to define any mediator acting as a signal between cells, regardless of cell type.
Cytokines are soluble polypeptide molecules with low molecular weight, more often glycosylated, produced by a wide variety of cells which do not seem to play a role in homeostasis in normal conditions, but which may be stimulated and released (even early) by surgery, trauma, infection, inflammation and cancer 1.
Most common cytokine-producing cells are: monocytes, macrophages, mastocytes, fibroblasts, B and T cells, endothelial cells, keratinocytes, smooth muscle cells, gastrointestinal parenchyma and endometrial stroma cells, in addition to neoplastic cells 1,2.
Cytokines may be generically classified as tumor necrosis factors (TNF), interleukines (IL), interferons (IFN) and colony stimulating factors. TNF and IL are response mediators in inflammation, infection and sepsis. INFs and colony stimulating factors act on hematopoietic systems (such as leukocyte activation, growth and differentiation regulation) and modulates the immune response (such as activation of inflammatory cells in response to antigen identification) 2.
Several cytokines have been identified and catalogued as TNF, IL-1 to 17, Platelet Activation Factor (PAF) e IFN.
This study aimed at reviewing and summarizing current information about cytokines, especially those related to pain and anesthetic techniques.
Cytokines differ from endocrine hormones for being produced by several cell types and for acting mostly locally or by cell to cell communication. When excessively produced they reach blood stream and act as hormones. A cell response to a certain cytokine depends on local peptide concentration as well as on the cell type. The same cytokine may act on several cell types producing different responses; in addition, they may have multiple effects on the same cell 1,3.
These mediators are responsible for local or systemic responses, generating immune, metabolic, hemodynamic, endocrine and neural changes. They may activate beneficial biological responses, such as antimicrobial function stimulation, wound healing, myelostimulation and substrate mobilization. However, excessive cytokine secretion is associated to deleterious effects, such as hypotension, organ failure and death 4.
Cytokines are extremely potent (act in picomolar concentrations) and very often influence synthesis and action of other cytokines 3.
These substances act by binding to specific receptors on the target-cell surface. This binding leads to intracellular changes through the activation of transducing pathways, mostly involving phosphorylation. Initial cytokine signal is amplified by second messenger-type systems, among them c-AMP, phosphokinase A, phospholipases and others. This is an important process for induction of qualitative and quantitative changes in the genetic expression responsible for cytokine local and systemic responses modulation 1.
There are several cytokine receptors grouped in families, such as immunoglobulin, interferon and neuronal growth factor receptors. Others are similar to the a-adrenergic receptor (helicoidal structure in seven a-helices) and there are those acting as transport binding proteins. The receptor-cytokine affinity is variable and a cytokine may have affinity for more than one family 3.
Tumor Necrosis Factors (Cachectin, Cachexin)
TNFs exist as two antigenically different polypeptides, namely a-TNF and b-TNF. They are primarily produced by macrophages, but a wide variety of other cells are associated to their production, such as monocytes, Kupffer cells, mastocytes and lymphocytes 5-7.
The maximal biological response of TNF occurs with the occupation of a small number of receptors, around 5% to 10% 8. TNFs plasma half-life is short, from 14 to 18 minutes in humans, being metabolized in liver, GI tract and kidney. Endotoxins are the most potent stimulus for their release in the blood stream 7, and may be early detected after the onset of a systemic infection 9. They are also seen in the plasma of cancer patients, following thermal aggression, in kidney transplant rejection and in fatal liver failure 10.
They are endogenous pyrogens acting on the hypothalamohypophysial axis 11, with important immunostimulating actions to fight microorganism invasion, causing neutrophil release, superoxide and lysozome production and macrophage activation (which participate in intracellular viral replication inhibition).
TNFs are related to metabolic changes, such as glucose transmembrane transportation increase, glycogenolysis, protein breakdown in skeletal muscles and trigliceryde and plasma free fatty acid increase resulting in hyperlipidemia with exaggerated body fat loss, seen in infections and other catabolic processes. They also cause a decrease in iron and zinc serum levels. Clinically, they lead to deep anorexia and contribute for the development of cachexia 2,6.
TNF stimulates endothelial surface coagulation, increases vascular patency 12 and acts as a growth factor stimulating the proliferation of microvessels and fibroblasts, thus impacting healing.
IL-1 is also found in two different biochemical forms (IL-1a and IL-1b) and both molecules activate the same receptor and share several biological activities. IL-1b is predominant 13.
IL-1 is primarily synthesized as from monocytes and macrophages, in addition to other cells, such as keratinocytes, endothelial cells, neutrophils and B lymphocytes 13. Similar to TNF, circulating half-life of this cytokine is short; approximately 6 to 10 minutes 10.
Endotoxin is the primary stimulator for IL-1 release, but TNF and IL-1 itself may stimulate its production 6,13. Its circulating levels are increased in septic, burnt, rheumatoid arthritis, transplant rejection and post-bypass patients, and in purpura and Kawasaki syndrome children 14-19.
It is an endogenous pyrogen 20 that increases prostaglandin E2 synthesis in the hypothalamus and is involved in anorexia. It significantly stimulates myelopoiesis in a direct or indirect way, through myelopoietic growth factors. It has metabolic effects, especially on liver protein balance promoting skeletal muscle proteolysis with the release of aminoacids. It induces iron and zinc serum levels decrease by increasing the release of proteins binding to those minerals, as well as by stimulating their uptake by reticuloendothelial liver system 2,3,10.
It has been initially described as interferon-b2, hepatocyte-stimulating factor, B cells differentiation factor and hybridoma/plasmocytoma growth factor. The name IL-6 was proposed in 1986/87. In 1988 there has been a uniformity consensus and the name IL-6 was proposed in 1988, during the New York Science Academy/National Cancer Research Foundation Meeting 21-23.
IL-6 is a glucoprotein composed of 212 aminoacids with molecular weight between 20-30 kDa produced by several cell types being monocytes and macrophages, endothelial cells and fibroblasts its major source, especially during inflammatory responses 14,23,24.
Several tumor cell strains are associated to the spontaneous production of such cytokine, such as myelomas, leukemias, myxomas, astrocytomas, glioblastomas, osteosarcomas and carcinomas (vesical, epidermoid, uterine and renal) 21,24-26.
IL-6 has been detected in CSF and sinovial fluid during central nervous system bacterial and viral inflammation and inflammatory arthritis, making us believe that other astroglia, microglia and synoviocytes may be IL-6 sources during local inflammation 9,27,28.
In monocytes and macrophages IL-6 biosynthesis may be especially stimulated by bacterial toxins, but there is IL-6 production by peripheral monocytes after IL-1 stimulation. In fibroblasts and endothelial cells, endogenous cytokines IL-1 and TNFa play an important role in IL-6 production by acting through two second-messenger systems: protein-kynase-C and cyclic AMP. So, IL-1 and TNFa would be responsible for IL-6 biological effects 29-33.
Intraventricular IL-1 in experimental animals resulted in IL-6 secretion, with high plasma levels indicating that the brain may effectively induce IL-6 synthesis and showing the existence of a binding pathway between the encephalon and periphery, thus explaining how diseases confined to the central nervous system may cause a systemic immune response 34.
There is an IL-6 specific receptor which is best defined as a complex made up of a receptor protein structure with molecular weight of 80 kd (IL-6r) and a transducer glucoprotein (gp-130). IL-6 has a low affinity for IL-6r, but in the presence of gp-130 the affinity is high with the dimerization of such protein, which seems to be an important first step for transduction 35,36.
Circulating IL-6 levels can be found during surgical trauma, in septic or burnt patients, in transplant rejection and in cancer patients or those with chronic diseases such as systemic lupus erythematosus and rheumatoid arthritis 27,28,37-39.
IL-6 is recognized as the major liver protein synthesis mediator in the acute phase of inflammatory reaction and is responsible for several endocrine and metabolic changes seen during surgical stress response 21,24,40,41. It works as endogenous pyrogen and acts by releasing ACTH that stimulates glucocorticoid synthesis by adrenocortical cells. On one side, steroids increase cytokine effects on liver protein synthesis, but on the other, they have a clear inhibitory effect on the synthesis of the same cytokines acting as a counter-regulator 41.
It has a role in hematopoiesis leading to the growth of primary hematopoietic parent-cells 21,23. It is related to megakaryocyte maturation and proliferation increase. Thrombocytosis seen in some diseases with IL-6 increase, such as rheumatoid arthritis and heart myxoma, evidences IL-6 role as potent thrombopoietic factor 42.
IL-6 has an anti-neoplastic action for myeloid tumor cells and ovary, breast and renal carcinomas, suggesting a potential role in cancer therapy 23,43.
It is one of the largest circulating cytokines in catabolic states. Human recombinant IL-6 infusion (IL-6rh) in metastatic renal cancer patients induces a hypermetabolic state, characterized by increases in body temperature, energy waste, norepinephrine, glucagon, cortisol plasma concentrations, glucose and free fatty acids. The authors suggest that IL-6 is a major metabolic response mediator and that several previous findings attributed to TNF may in fact be caused by TNF-induced IL-6 secretion 44.
This cytokine must be mentioned because of its marked immunosupressant effects, deeply decreasing macrophage activation and inhibiting their interleukin secretion ability 1,45. It has been described as cytokine synthesis inhibiting factor 11. It counter-regulates cell responses suppressing PGE2 and pro-inflammatory cytokine production.
CYTOKINES AND SURGICAL TRAUMA
Surgical stress is responsible for several inflammatory and metabolic responses including thermogenesis, hyperglycemia, leucocytosis, tachycardia, tachypnea, fluid sequestration, loss of muscle proteins, acute phase protein synthesis increase and iron and zinc plasma levels decrease. For many years, such generalized response was considered beneficial for defending the body against aggressions, but recent studies have suggested that when excessive it may cause organic damage 46. Cytokines are considered major mediators of such responses, which chiefly involve TNF, IL-1 and IL-6, but this, of course, does not exclude the classic stress hormone responses (cortisol, catecholamines). High cytokine circulating levels seem to be involved in postoperative complications and recovery delay, and the attenuation of those events would be associated to a decrease in the frequency of complicating factors 47.
The acute inflammatory reaction is an important response to homeostatic changes (including surgeries, traumas, neoplasias, infections and other disorders), and consists of local and systemic reactions aiming at limiting tissue injury, isolating and destroying microorganisms and activating the healing process needed to reestablish body functions balance 41. Local reactions are seen at injury sites and encompass platelet aggregation, clot formation, vasodilation, granulocytes and mononuclear cells accumulation and activation and release of interleukins. Systemic reactions include fever, behavioral changes (sleep, poor physical condition), pain, leucocytosis, increased hemosedimentation speed, increased ACTH and glucocorticoid secretion, decreased iron and zinc plasma levels, negative nitrogen balance, complement and coagulation cascade activation and a dramatic change in some plasma protein concentrations, namely acute phase proteins synthesized by the liver. These proteins act as inflammatory mediators of immune responses and may be considered tissue injury markers, such as the C-reactive protein. In man, during acute inflammatory response, there is an increase in C-reactive, A and P serum amyloids, fibrinogens, haptoglobins, ceruloplasmins and acid glucoproteins, as well as a decrease in albumin and transferrin 48,49.
This process starts at the trauma site where macrophages and monocytes stimulate cytokine release, especially IL-1 and TNF, which are considered primary interleukins. By themselves, they cause further cytokine release, especially IL-6, which has been considered a major acute phase liver protein stimulator and organic defense response mediator 41.
Wortel et al. (1993) 50 have investigated body response after abdominal surgeries (pancreatoduodenectomy) by dosing peripheral and portal blood cytokines draining from the surgery site. A major IL-6 increase in portal blood with significantly lower peripheral levels was observed. No significant TNF increase was detected, showing that IL-6 is the major endogenous mediator of postoperative response. This was confirmed by other authors 51,52, who proposed a lack of consistent IL-1 and TNFa systemic response after surgical trauma.
Cruickshank et al. (1990) 53 have observed an association between trauma extension and IL-6 circulating levels. Patients submitted to minor procedures, such as exeresis of varicose veins and partial thyroidectomy, had a significantly lower IL-6 increase as compared to major procedures, such as colorectal and aorta aneurysm resections. Responses depended on the injury site and extra-abdominal interventions produced lower IL-6 levels as compared to intra-abdominal procedures involving intestinal manipulation (which may be a potent stimulus for IL-6 release). In the study, IL-6 serum levels increased 2 to 4 hours after incision and peaked within 6 to 12 hours. The authors concluded that IL-6 is not only a tissue injury sensory marker, but also suffers early changes.
Comparing endocrine-metabolic and inflammatory responses after open or laparoscopic cholecystectomy, Joris et al. (1992) 54 have observed a significantly lower IL-6 increase in the laparoscopic group, thus confirming the above mentioned findings. Changes in epinephrine, norepinephrine and cortisol plasma concentrations were similar in both groups, but the laparoscopic group showed a better and early recovery. Authors have emphasized the association of lower IL-6 levels with a better postoperative recovery 55. A similar study was performed showing that laparoscopic cholecystectomy causes significantly lower glucose, IL-6 and C-reactive protein changes, without differences in cortisol and albumin levels 56. The video-assisted groups showed less fatigue and earlier return to daily activities, with lower IL-6 serum levels.
The role of cytokines has been reported in cardiac surgeries 57-59, especially with cardiopulmonary bypass, where inflammatory response and immune dysfunction by the combination of intense surgical trauma, hypothermia, hemodilution and cell movement through oxygenator membranes and bearings (causing cell damage) are important. Cytokines release in response to inflammation in such surgeries is dominated by IL-6, IL-8, and IL-1 and, in a lesser degree, by TNF. In general it is a transient non deleterious response because it is counterbalanced by an anti-inflammatory response of other cytokines and mediators. IL-10 has a fundamental role in this anti-inflammatory response, as well as IL-4, IL-11, IL-1 receptor antagonist (IL-1 ra), TNF soluble receptors (TNFsr), ACTH and cortisol, which are released to interact and attenuate excessive imunostimulation 60.
According to some authors 15, after cardiopulmonary bypass there is an immediate decrease in pro-inflammatory cytokine plasma concentrations (partially explained by hemodilution); however, during and after bypass, there is a marked increase in anti-inflammatory cytokines. This anti-inflammatory response starts with IL-10 release after aorta declamping and is followed by an IL-1ra and TNFsr increase. The concept of cytokines balance (pro and anti-inflammatory) seems to be implicated in the prognosis of patients submitted to such surgeries.
It is worth stressing that in patients submitted to blood transfusion, interleukin levels are different for allogenic and autologous techniques. Major intra or postoperative blood losses are in general allogenic blood responses. However, preoperative autologous blood collection is becoming increasingly common aiming at minimizing allogenic transfusions related to viral disease transmission and immune reactions. Autologous blood, however, has large cytokine concentrations and anaphylaxis-related toxins. There is a predominance of IL-6 and IL-8, indicating an inflammatory response. The lower incidence of such cytokines in alogenous blood may result from the immune depression caused by this type of transfusion, as documented in a study where survival improvement was observed in previously transfused patients submitted to renal transplants, calling the attention for the central role of cytokines in rejection immune responses 61.
As to surgical wound healing, it must be reminded the important role of IL-6, which is involved in almost all stages of this process. This interleukin induces T cell proliferation, causes epithelial migration and contributes to fibroblasts response necessary for collagen deposition in immature granulation tissues 62. Significant IL-6 concentrations in surgery site have been documented, indicating that it is important for tissue repair 63.
CYTOKINES AND SEPSIS
Sepsis is a systemic inflammatory response resulting from infection and its severity is associated to body response intensity.
Several mediators have been related to septic syndrome, but many evidences suggest that cytokines are decisive factors for its pathophysiology, since their excessive production cause tissue injury, which may result in organ dysfunction. Four cytokines have been strongly related to sepsis: TNF-a, IL-1b, IL-6 and IL-8 64.
TNF-a may be detected in the plasma of several septic patients, and is related to fever, hemodynamic abnormalities, leucopenia, liver enzymes increase, coagulopathies and organ dysfunction. High and persistent plasma concentrations seem to indicate a poor prognosis 65.
IL-1b mimics several TNF-a biologic effects causing fever, hemodynamic changes, anorexia, discomfort, arthralgia, headache and neutrophilia. Studies have shown that IL-1b is increased in some septic patients and may be related to severity, but not to mortality 64.
IL-6 has also been detected in sepsis and was associated to a poorer prognosis 65. It has been related to increase in body temperature, heart rate, serum lactate, APACHE II scale (which evaluates severity) and to blood pressure and platelet count decrease, seeming to be the best indicator of cytokine cascade activation and of subsequent organ dysfunction and death 66.
IL-8 is a cytokine with chemotactic functions and its primary function is to activate and attract neutrophils to inflammation sites. Authors have found increased IL-8 plasma and broncho-alveolar smear levels in Adult Respiratory Distress Syndrome (ARDS) patients, associated to severe pneumonia and confirming the association of high IL-8 levels and neutrophil accumulation in the alveoli 67. Others have found high IL-8 concentrations in septic patients and have correlated them to mortality 68.
A complex cytokine action is associated to sepsis pathophysiology and its activation cascade block might be a promising treatment alternative. Anti-cytokine strategies, such as anti-TNF antibodies and IL-1 receptor antagonists have been studied, however without consistent results 69.
CITOKYNES AND PAIN
Nociceptive sensitization causing hyperalgesia is a common denominator for different types of pain. For this to occur, it is necessary the release of mediators that build a bridge between cell and tissue aggression and the development of local and systemic inflammatory events. Cytokines are known as mediators able to build such binding 70.
Immune systems participation is critical because several hyperalgesia-inducing peripheral events trigger immune cells that, by themselves, release pro-inflammatory cytokines. These stimulate peripheral nervous terminals activating the spinal cord dorsal horn and encephalon 71.
In animals, TNF-a, IL-1b, IL-6 and IL-8 produce hyperalgesia and TNF-a has an initial role in cytokine-releasing cascade activation 72. This would be responsible for prostaglandin-mediated hyperalgesia, but was not confirmed by other authors 73.
It is worth highlighting the hypothesis that vagal afferent terminations are activated by peripheral cytokines causing an increase in brain cytokines as a consequence of the solitary tract afferent nucleus activation. Descending pathways originating from this area are responsible for triggering different types of hyperalgesia. IL-1 produced by Kupffer cells would bind to abdominal paraganglia glomic cells which would form synapses with vagal afferent terminals responsible for transporting information to the central nervous system 71,73. Since cytokines do not cross blood-brain barrier because they are large lipophobic protein molecules, the vagal hypothesis is very attractive, but other mechanisms have been proposed in an attempt to explain how peripheral impulses reach the encephalon. One possibility is the binding to vascular cerebral endothelium receptors and then to periventricular regions with the release of neuromediators 74.
As to post nervous injury hyperalgesia, there are reports on the release of pro-inflammatory cytokines by macrophages invading the aggression site. Other involved cells, such as Schwam and glial cells, may also produce TNF, IL-1 and IL-8. Fagocytes have been held responsible for sensitivity changes and neural spontaneous aberrant activity observed in such cases 71.
Some substances capable of inhibiting inflammation-induced hyperalgesia, such as steroids, capsaicin, NSAIDs and morphine can also inhibit cytokine synthesis and release 75-78.
Since cytokine release is related to hyperalgesia, its blockade has been suggested as a potential pain treatment strategy 79. Cytokine-suppressing anti-inflammatory drugs (CSAI) are currently being studied and one of them, SKF 86002, has shown analgesic activity in acute and chronic pain models, suggesting that such drugs may become a new analgesic option for clinical use 80.
CYTOKINES AND ANESTHETIC TECHNIQUES
For many years, several anesthetic techniques have been studied aiming at evaluating their influence in surgical stress response, especially investigating the role of afferent impulses propagation and neuroaxis response. Investigators, however, were concentrated on classic endocrine hormone responses making cytokines and their role in tissue trauma response to be overlooked for a long time.
Recently several authors tryied to establish a correlation between cytokines, especially pro-inflammatory cytokines (mainly IL-6), and anesthetic techniques, more frequently epidural anesthesia, as well as opioids through different routes.
Naito et al. (1992) 81 have dosed adrenocorticotropic hormone (ACTH); cortisol and cytokine plasma levels in patients submitted to pacreatoduodenectomy and unilateral hip replacement, anesthetized with general anesthesia or general anesthesia associated to epidural anesthesia reaching T2-T4. Epidural anesthesia association has almost completely attenuated ACTH and cortisol response and no significant changes were observed in IL-6 and TNF-a in patients submitted to hip replacement. In abdominal surgeries, ACTH and cortisol, as well as cytokines remained high with the epidural association, which was unable to effectively suppress stress response. The authors suggested that not only neural afferent impulses originated in the surgery site, but also high TNF and IL-6 levels would stimulate ACTH and cortisol release causing such an important change during pancreatoduodenectomy that epidural anesthesia, even thoracic, was unable to block.
Schulze et al. (1992) 82 have evaluated patients submitted to colo-rectal resections who were randomly distributed to receive postoperative analgesia with morphine and acetaminophen (G-1) or methylprednisolone, spinal anesthesia, epidural with morphine and indomethacin (G-2). There were no postoperative pain and fever in Group 2, in addition to better pulmonary parameters and motility recovery. C-reactive protein, IL-6 and PGE2 increased in both groups, but were significantly lower in Group 2. The authors have attributed these effects to the anti-inflammatory action of glucocorticoid and indomethacin and to intense neural block.
Further studying epidural anesthesia ability to attenuate perioperative stress response, some authors 83 have not observed significant differences in hormone (catecholamines and cortisol), TNF, Il-1 and IL-6 concentrations in patients submitted to abdominal aorta surgery under general anesthesia followed by postoperative intravenous morphine analgesia, and those submitted to general/epidural anesthesia followed by postoperative epidural morphine analgesia. These results confirm a previous study on hysterectomies where epidural block association has not affected IL-6 plasma concentrations 84.
A study in obstetric anesthesia has shown that in Cesarean sections IL-6 levels increased, regardless of the anesthetic technique, and that in vaginal deliveries this increase was more pronounced 85. According to the authors, in prolonged labor, the excessive effort as well as the psychological stress and changes in myometrium contractility (which may be an IL-6 source), are related to the increase in IL-6 production.
Crozier et al. (1994) 86 have studied women submitted to abdominal hysterectomy under inhalational anesthesia with isoflurane and nitrous oxide (G1) or total venous anesthesia with alfentanil and propofol (G2). Interleukines 1 and 6 and cortisol were dosed before induction and up to 6 postoperative hours. IL-1 concentrations did not change during the study, but IL-6 and cortisol showed an early increase in Group 1 where mean plasma levels were also higher. Although IL-1 exerts a role in organic injury reactions, the study has only shown mild changes after surgical trauma. According to the authors, there may be a local IL-1 secretion, insufficient to cause an increase in peripheral blood, but which may stimulate IL-6 production, which, in turn, increases after a short delay, according to its synthesis kinetics depending on genetic expression and messenger RNA production. The authors concluded that reduction in the IL-6 release (to surgical stress) by alfentanil-propofol anesthesia as compared to inhalational anesthesia may be a direct effect of the drugs or an indirect action through opioid-mediated hormonal changes.
Further comparing inhalational and intravenous techniques, the authors evaluated their effects on hysterectomies under anesthesia with isoflurane (G1) or propofol and alfentanil in continuous infusion (G2), analyzing not only pro-inflammatory cytokines (TNF, IL-6), but also anti-inflammatory components (IL-10 and IL-1ra) 16. TNF-a levels remained low throughout the study, but all patients had significant IL-6, IL-10 and IL-1ra increases. IL-6 levels were similar for both groups while IL-10 levels were significantly higher in the intravenous group. There were no significant differences in IL-1ra. According to the authors, this study has shown pro and anti-inflammatory components of cytokine response to abdominal surgery and has also indicated that the anesthetic technique affects those proteins balance. Assuming that calcium has an important role in cytokine regulation, that some cell strains double their IL-10 production when cultivated in a medium with high concentrations of this ion and that propofol, but not isoflurane, when added to the culture causes and immediate and transient intracellular calcium increase (probably by stock release), the authors concluded that the difference in cytokine production between groups was related to changes in intracellular calcium levels. Another hypothesis would be that after isoflurane, but not after propofol, there would be a decrease in T lymphocytes, which are able to produce IL-10. The authors suggest that intravenous anesthesia with propofol may promote anti-inflammatory cytokine release, while the addition of opioid infusion may suppress inflammatory cytokine production, concluding that the ability to change cytokine balance through the anesthetic technique may have implications in high-risk patients, including those at risk of multiple organ failure.
Other authors have evaluated the effects of 3 or 15 µg.kg-1 fentanyl in IL-6, IL-8, C-reactive protein, cortisol and glucose concentrations in hysterectomies and have not observed significant differences among groups 87.
Comparing high and low opioid doses in myocardial revascularization, authors have analyzed IL-6, IL-8 and IL-10 behavior and have not seen anesthesia-related changes in cytokine production 60. However, when associating low ketamine doses (0.25 mg.kg-1) to general anesthesia with high fentanyl doses in a randomized double-blind study of elective myocardial revascularization, other authors have found a marked decrease in IL-6 levels immediately after cardiocirculatory bypass which lasted for 48 hours and their concentrations were significantly lower for seven postoperative days as compared to the control group 88.
Cortisol production during surgeries may be suppressed by etomidate, a drug widely used in anesthesia. Investigating the relation between cortisol and IL-6 levels and etomidate in patients submitted to abdominal hysterectomy, some authors have observed significantly higher IL-6 levels in patients under etomidate as compared to the control group (receiving thiopental). There was a significant difference in cortisol serum levels between groups, which were not beyond baseline levels in the etomidate group up to 6 hours after the beginning of the procedure 89.
Preoperative subcutaneous bupivacaine infiltration may decrease postoperative pain and stress response. This hypothesis was tested in a study with 29 patients submitted to hysterectomy and randomly distributed in three groups: group 1 received 30 ml of 0.25% bupivacaine with epinephrine; group 2 received 30 ml saline; and group 3 was not infiltrated before surgery. IL-6 and cortisol were measured 72 hours after skin incision. Postoperative intravenous morphine analgesia was patient-controlled. Morphine consumption was significantly lower in the bupivacaine group, but IL-6 and cortisol levels were increased in all groups, without statistical differences among them 90.
So, it is clear that cytokines have a fundamental role as metabolic, hormonal, immune and hematological response mediators; that there is a therapeutic potential for their expression block; and that anesthesia may interfere in their activation. However, several questions are still to be answered and further studies are needed to explain cytokine actions not only for experimental, but also for clinical purposes.
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Submitted for publication April 20, 2001 *
Received from Disciplina de Anestesiologia, Dor e Terapia Intensiva da Universidade
Federal de São Paulo, Escola Paulista de Medicina (UNIFESP EPM), São
Accepted for publication July 23, 2001
Submitted for publication April 20, 2001
* Received from Disciplina de Anestesiologia, Dor e Terapia Intensiva da Universidade Federal de São Paulo, Escola Paulista de Medicina (UNIFESP EPM), São Paulo, SP